title: Complex I inhibition in the visual pathway induces disorganization of the node of Ranvier.
abstract: Mitochondrial defects can have significant consequences on many aspects of neuronal physiology. In particular, deficiencies in the first enzyme complex of the mitochondrial respiratory chain (complex I) are considered to be involved in a number of human neurodegenerative diseases. The current work highlights a tight correlation between the inhibition of complex I and the state of axonal myelination of the optic nerve. Exposing the visual pathway of rats to rotenone, a complex I inhibitor, resulted in disorganization of the node of Ranvier. The structure and function of the node depend on specific cell adhesion molecules, among others, CASPR (contactin associated protein) and contactin. CASPR and contactin are both on the axonal surfaces and need to be associated to be able to anchor their myelin counterpart. Here we show that inhibition of mitochondrial complex I by rotenone in rats induces reactive oxygen species, disrupts the interaction of CASPR and contactin couple, and thus damages the organization and function of the node of Ranvier. Demyelination of the optic nerve occurs as a consequence which is accompanied by a loss of vision. The physiological impairment could be reversed by introducing an alternative NADH dehydrogenase to the mitochondria of the visual system. The restoration of the nodal structure was specifically correlated with visual recovery in the treated animal.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Marella
authors.forename: Gaurav
authors.initials: G
authors.lastname: Patki
authors.forename: Akemi
authors.initials: A
authors.lastname: Matsuno-Yagi
authors.forename: Takao
authors.initials: T
authors.lastname: Yagi
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D058966:Contactins / Q000235:genetics / Q000378:metabolism; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology*; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism*; D007306:Insecticides / Q000494:pharmacology; D008297:Male; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology*; D011901:Ranvier's Nodes / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D051381:Rats; D020318:Rats, Long-Evans; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013997:Time Factors; D014795:Visual Pathways / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; C105177:Cntnap1 protein, rat; D058966:Contactins; D007306:Insecticides; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D012402:Rotenone; D042967:Electron Transport Complex I
keywords: 7,8-dihydro-8-oxo-deoxyguanine; 8-oxo-dG; AAV2-NDI1; Mitochondrial complex I; Myelination; Ndi1; Neurodegenerative disease; Node of Ranvier; Optic neuropathy; RGC; ROS; SC; VC; Visual pathway; adeno-associated virus carrying the NDI1 gene; complex I; internal rotenone-insensitive NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria; mitochondrial DNA; mitochondrial proton-translocating NADH-quinone oxidoreductase; mtDNA; reactive oxygen species; retinal ganglion cell; superior colliculus; visual cortex